ClinVar Miner

Submissions for variant NM_000137.3(FAH):c.1009G>A (p.Gly337Ser) (rs80338900)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000012644 SCV000220983 likely pathogenic Tyrosinemia type I 2014-12-24 criteria provided, single submitter literature only
Invitae RCV000012644 SCV000828028 pathogenic Tyrosinemia type I 2018-04-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 337 of the FAH protein (p.Gly337Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs80338900, ExAC 0.03%). This variant has also been reported as homozygous or in combination with other FAH variants in individuals affected with tyrosinemia type 1 (PMID: 8076937, 9633815, 24756054, 22554029).  This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 11869). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have shown that this missense change causes aberrant splicing of FAH mRNA in patient fibroblasts (PMID: 8076937). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012644 SCV000032879 pathogenic Tyrosinemia type I 1995-02-01 no assertion criteria provided literature only
GeneReviews RCV000012644 SCV000040446 pathologic Tyrosinemia type I 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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