Submissions for variant NM_000277.3(PAH):c.1159T>C (p.Tyr387His)

dbSNP: rs62517194

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001789754	SCV002032191	likely pathogenic	Phenylketonuria	2020-08-17	reviewed by expert panel	curation	The c.1159T>C (p.Tyr387His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011, 21890392). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.L48S, p.Y204X (PMID: 21147011); p.T323del (PMID: 9169088); c.754C>T, p.Arg252Trp (PMID: 21890392); p.Ala395Pro (PMID: 23357515); p.R261Q, c.782G>A (PMID: 23690520). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001789754	SCV003441281	pathogenic	Phenylketonuria	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 387 of the PAH protein (p.Tyr387His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 23357515, 23856132, 32668217). ClinVar contains an entry for this variant (Variation ID: 102539). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001789754	SCV004209688	pathogenic	Phenylketonuria	2024-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001789754	SCV005039025	pathogenic	Phenylketonuria	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1159T>C (p.Tyr387His) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes (gnomAD). c.1159T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Dobrowolski_2007, Kostandyan_2011, Sterl_2013, Pilotto_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17502162, 21890392, 30706953, 22526846). ClinVar contains an entry for this variant (Variation ID: 102539). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004542806	SCV005040821	pathogenic	Malignant tumor of breast	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1159T>C (p.Phe387Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251224 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1159T>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088772	SCV000119357	not provided	not provided		no assertion provided	not provided