ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with orofaciodigital syndrome I (MIM#311200). (I) 0110 - This gene is associated with X-linked disease. Most conditions associated with this gene are X-linked recessive, however orofaciodigital syndrome I (MIM#311200) is X-linked dominant. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other variants predicted to result in a loss of function have previously been reported in individuals with orofaciodigital syndrome I (MIM#311200) (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple individuals with orofaciodigital syndrome I (MIM#311200), with both de novo and familial inheritance (HGMD, LOVD, PMID: 18546297). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as 702insA using alternate nomenclature; This variant is associated with the following publications: (PMID: 18546297, 19876934, 12595504)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000041143 / PMID: 12595504). The variant was detected at ~19% allele frequency and was identified as a potential mosaic variant. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

The OFD1 c.710dupA variant is predicted to result in a frameshift and premature protein termination (p.Tyr238Valfs*2). This variant was reported in individuals with oral-facial-digital syndrome I (see for example, reported as 702insA at Romio et al. 2003. PubMed ID: 12595504 with clinical information at Feather et al. 1997. PubMed ID: 9215688; de novo at Table S6 of El Naofal et al. 2023. PubMed ID: 36703223). This variant is reported in 0.0071% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in OFD1 are expected to be pathogenic. This variant is interpreted as pathogenic.