Submissions for variant NM_000137.4(FAH):c.841C>A (p.Pro281Thr)

gnomAD frequency: 0.00010  dbSNP: rs199820704

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000268513	SCV000394052	uncertain significance	Tyrosinemia type I	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000730663	SCV000858416	uncertain significance	not provided	2017-11-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000268513	SCV001421518	uncertain significance	Tyrosinemia type I	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the FAH protein (p.Pro281Thr). This variant is present in population databases (rs199820704, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of FAH-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 317214). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breakthrough Genomics, Breakthrough Genomics	RCV000730663	SCV005193949	uncertain significance	not provided		criteria provided, single submitter	not provided
Fulgent Genetics, Fulgent Genetics	RCV000268513	SCV005635345	uncertain significance	Tyrosinemia type I	2024-05-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000268513	SCV002089839	uncertain significance	Tyrosinemia type I	2018-06-24	no assertion criteria provided	clinical testing