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NM_001014437.3(CARS1):c.1271G>A (p.Arg424His) AND Microcephaly, developmental delay, and brittle hair syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Oct 21, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001102528.8

Allele description [Variation Report for NM_001014437.3(CARS1):c.1271G>A (p.Arg424His)]

NM_001014437.3(CARS1):c.1271G>A (p.Arg424His)

Gene:
CARS1:cysteinyl-tRNA synthetase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.4
Genomic location:
Preferred name:
NM_001014437.3(CARS1):c.1271G>A (p.Arg424His)
HGVS:
  • NC_000011.10:g.3019263C>T
  • NM_001014437.3:c.1271G>AMANE SELECT
  • NM_001194997.2:c.1271G>A
  • NM_001378136.1:c.1061G>A
  • NM_001378137.1:c.992G>A
  • NM_001378138.1:c.992G>A
  • NM_001378139.1:c.992G>A
  • NM_001378140.1:c.746G>A
  • NM_001751.6:c.1022G>A
  • NM_139273.4:c.1022G>A
  • NP_001014437.1:p.Arg424His
  • NP_001181926.1:p.Arg424His
  • NP_001365065.1:p.Arg354His
  • NP_001365066.1:p.Arg331His
  • NP_001365067.1:p.Arg331His
  • NP_001365068.1:p.Arg331His
  • NP_001365069.1:p.Arg249His
  • NP_001742.1:p.Arg341His
  • NP_644802.1:p.Arg341His
  • NC_000011.9:g.3040493C>T
  • NM_001751.5:c.1022G>A
  • NR_036542.2:n.1374G>A
  • NR_165428.1:n.1374G>A
  • NR_165429.1:n.1078G>A
  • NR_165430.1:n.1078G>A
Protein change:
R249H; ARG341HIS
Links:
OMIM: 123859.0002; dbSNP: rs777861752
NCBI 1000 Genomes Browser:
rs777861752
Molecular consequence:
  • NM_001014437.3:c.1271G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001194997.2:c.1271G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378136.1:c.1061G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378137.1:c.992G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378138.1:c.992G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378139.1:c.992G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378140.1:c.746G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001751.6:c.1022G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139273.4:c.1022G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_036542.2:n.1374G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_165428.1:n.1374G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_165429.1:n.1078G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_165430.1:n.1078G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Microcephaly, developmental delay, and brittle hair syndrome
Identifiers:
MONDO: MONDO:0030047; MedGen: C5394425; OMIM: 618891

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001259206OMIM
no assertion criteria provided
Pathogenic
(Aug 12, 2021) 		germlineliterature only

Kuo, M. E., Theil, A. F., Kievit, A., Malicdan, M. C., Introne, W. J., Christian, T., Verheijen, F. W., Smith, D. E. C., Mendes, M. I., Hussaarts-Odijk, L., van der Meijden, E., van Slegtenhorst, M., and 11 others Cysteinyl-tRNA synthetase mutations cause a multi-system, recessive disease that includes microcephaly, developmental delay, and brittle hair and nails. Am. J. Hum. Genet. 104: 520-529, 2019.,

SCV002016190Genetic Medico-Diagnostic Laboratory Genica
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Oct 21, 2021) 		maternalclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedmaternalyes1not providednot provided1yesclinical testing

Citations

PubMed

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails.

Kuo ME, Theil AF, Kievit A, Malicdan MC, Introne WJ, Christian T, Verheijen FW, Smith DEC, Mendes MI, Hussaarts-Odijk L, van der Meijden E, van Slegtenhorst M, Wilke M, Vermeulen W, Raams A, Groden C, Shimada S, Meyer-Schuman R, Hou YM, Gahl WA, Antonellis A, Salomons GS, et al.

Am J Hum Genet. 2019 Mar 7;104(3):520-529. doi: 10.1016/j.ajhg.2019.01.006. Epub 2019 Feb 26.

PubMed [citation]
PMID:
30824121
PMCID:
PMC6407526

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From OMIM, SCV001259206.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature onlynot provided

Description

In a 35-year-old Dutch woman (family 2) with microcephaly, developmental delay, and brittle hair syndrome (MDBH; 618891), Kuo et al. (2019) identified compound heterozygosity for a c.1022G-A transition (c.1022G-A, NM_001751.5) in the CARS1 gene, resulting in an arg341-to-his (R341H) substitution at a highly conserved residue, and a c.1138C-T transition, resulting in a gln380-to-ter (Q380X) substitution. Both mutations occurred within the catalytic domain, and the truncation was predicted to result in complete loss of the anticodon-binding domain. The proband's unaffected parents were each heterozygous for 1 of the mutations, which were both present at low frequency in the gnomAD database, but only in heterozygous state (minor allele frequencies, 0.00004 and 0.000005, respectively). Immunoblot analysis of patient fibroblasts showed a significant reduction in the amount of full-length CARS protein compared to control cells, and no truncated protein was detected. Aminoacylation reactions on protein lysates from patient fibroblasts showed an approximately 80% reduction in CARS activity compared to controls, consistent with a loss-of-function effect for the variants. Yeast complementation assay, using a haploid yeast strain in which the endogenous yeast CARS ortholog had been deleted, demonstrated that the Q380X mutant did not support any yeast cell growth, in contrast to wildtype rescue of viability, confirming loss of function with the Q380X variant. The R341H mutant was associated with severely reduced but not ablated yeast cell growth, and aminoacylation assays revealed a 50% reduction in activity with the R341H mutant compared to wildtype CARS.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Genetic Medico-Diagnostic Laboratory Genica, SCV002016190.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providedyesclinical testing PubMed (2)

Description

Kuo et al., 2019 (PMID:30824121) performed functional analysis of the variant and classified it as pathogenic for Microcephaly, developmental delay, and brittle hair syndrome (OMIM:618891). The variant was observed in compound heterozygosity with CARS1:c.1108C>T (NM_001751.6), which is described as a variant with uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyes1not provideddiscovery1not providednot providednot provided

Last Updated: Jun 23, 2024