Submissions for variant NM_000137.4(FAH):c.424A>G (p.Arg142Gly)

dbSNP: rs1420414848

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192778	SCV001361113	pathogenic	Tyrosinemia type I	2021-01-29	criteria provided, single submitter	clinical testing	Variant summary: FAH c.424A>G (p.Arg142Gly) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.424A>G has been reported in the literature in a family with three affected siblings (homozygous for the variant) who developed chronic liver disease and hepatocellular carcinoma without elevated tyrosine or succinylacetone (Blackburn_2016). The unaffected parents and two other unaffected siblings were determined to be carriers of the variant. These data indicate that the variant is very likely to be associated with disease. At least one publication showed that this variant results in loss of enzyme activity (Blackburn_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001192778	SCV004195909	pathogenic	Tyrosinemia type I	2022-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV001192778	SCV004297662	likely pathogenic	Tyrosinemia type I	2023-04-28	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects FAH function (PMID: 27397503). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAH protein function. ClinVar contains an entry for this variant (Variation ID: 928613). This missense change has been observed in individual(s) with clinical features of FAH-related conditions (PMID: 27397503). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 142 of the FAH protein (p.Arg142Gly).
GeneReviews	RCV001192778	SCV001981680	not provided	Tyrosinemia type I		no assertion provided	literature only